Long-term (1-year) experience with
LDS 100 in the treatment of men and
women with androgenetic alopecia

Background. LDS 100 is
indicated for the treatment of men
and women with androgenetic alopecia
(male pattern hair loss, MPHL and
female pattern hair loss, FPHL).
However, the long-term (> 1 year)
efficacy of LDS 100 in this
population has not been previously
reported. Objectives.
To assess the efficacy and safety of
LDS 100 in men and women with
androgenetic alopecia compared to
treatment with placebo device over 1
year. Methods.
In 6 months, 240 men with MPHL and
80 women with FPHL were randomized
to receive LDS 100 treatment or
placebo treatment. Men and women
continued in up to 1 year, placebo
controlled extension studies.
Efficacy was evaluated by hair
counts, patient and investigator
assessments, and panel review of
clinical photographs. Results.
Treatment with LDS 100 led to
durable improvements in scalp hair
over 1 year (p < 0.001 versus
placebo, all endpoints), while
treatment with placebo led to
progressive hair loss. LDS 100 was
generally well tolerated and no new
safety concerns were identified
during long-term use. Conclusions.
In men with MPHL and in women with
FPHL, long-term treatment with LDS
100 over 1 year was well tolerated,
led to durable improvements in scalp
hair growth, and slowed the further
progression of hair loss that
occurred without treatment.

Androgenetic
alopecia (male pattern hair loss,
MPHL and female pattern hair loss,
FPHL) occurs in men and women with
an inherited sensitivity to the
effects of androgens on scalp hair.
The disorder is characterized by
loss of visible hair over areas of
the scalp due to progressive
miniaturization of hair follicles.
MPHL does not occur in men whit
genetic deficiency of the type 2
5α-reductase (5αR) enzyme, which
converts testosterone (T) to
dihydrotestosterone (DHT),
implicating DHT in the pathogenesis
of this condition. Of the two 5αR
isoenzymes in man, Type 1
predominates in sebaceous glands of
the skin, including scalp, while
Type 2 is present in hair follicles,
as well as the prostate. In the
androgenetic alopecia also occurs a
reduction of the synthesis of the
mRNA and the DNA with diminution of
the cellular metabolism.

The infrared
radiation of LDS 100 (940 nm)
penetrates in depth. It transits
without producing great
photo-biological effects; if not
there where it comes to be absorbed
then in the interface between the
epidermis and the dermis. The
photo-biological bases of
therapeutic use of infrared
radiation re-engage themselves in a
mechanism “fallen” on various
structures. There is a
photoreception at the mitochondrial
level. The radiation is absorbed at
the level of the respiratory chain (cytochromes,
oxidase cytocrome, dehydrogenase
flowin) with the consequent
activation of the respiratory chain
and further the activation of the
NAD (nicotinamide adenine
dinucleotide).

At the
cellular membrane level there is an
increase in the activity of the
enzyme Na/K ATPasis, which in turn
acts on the flow of Ca+. At this
point one has a transduction and an
amplification of the stimulus in the
cellular ambit, with the activation
of the cyclical nucleotides which
modulate the synthesis of the mRNA
and the DNA.
The final photo-response is the
bio-stimulation at the various
levels of the cellular metabolic
structure. The biological activation
spreads from cell to cell with
chemical transmissions. The infrared
light increases the cellular
metabolism accompanied by an
augmentation of the capillary
vascular bed of the radiant zone
with an increase also in the supply
of oxygen.
Studies in man with MPHL and women
with FPHL showed that LDS 100 had
utility in this disorder.

Randomized
placebo-controlled trials
demonstrated that treatment whit LDS
100 produced significant
improvements in scalp hair growth,
slowed the further progression of
hair loss that occurred without
treatment and led to increased
patient satisfaction with the
appearance of their scalp hair.

LDS 100 use is
contraindicated in women when they
are or may potentially be pregnant
and in subjects with pace-maker or
other metallic devices, or those
with acute phlebitis, serious
arterial hypertension, neurogical
illnesses, heightened cardiopathy,
dermatitis and dermatosis.

Materials and methods

Study
population

Men aged 18 to
50 years, whit mild to moderately
severe vertex MPHL according to a
modified Norwood/Hamilton
classification scale (II vertex, III
vertex, IV or V), were enrolled.
Women aged 18 to 50 years, with mild
to moderately severe vertex FPHL
according to a Ludwig classification
scale (I, II or III), were enrolled.
Principal exclusion criteria
included significant abnormalities
on screening physical examination or
laboratory evaluation, surgical
correction of scalp hair loss,
topical Minoxidil use within
one-year, use of drugs with
androgenetic or antiandrogenetic
properties, use of finasteride or
other 5αR inhibitors, or alopecia
due to other causes. Men and women
were instructed not to alter their
hairstyle or dye their hair during
the studies.

Study
protocols

One initial,
6-months randomized, double-blind,
placebo controlled studies were
initiated, and both were continued
as 1 consecutive, 6-months,
double-bind, placebo-controlled
extension studies. The objectives of
the controlled extension studies
were to determine the effect of
long-term use of LDS 100, the effect
of delaying treatment by one year,
and the progression of MPHL in men
and FPHL in women not receiving
active treatment.

6-months initial studies
Following a screening procedure,
study subjects entered a 2 week,
single-blind, placebo run-in period.
All men and women received study
shampoo (Claim 3S®) for
standardization of shampoo used and
for prophylaxis of seborrheic
dermatitis, which might affect scalp
hair growth. Subjects (240 men and
80 women) were than randomized to
LDS 100 (2 times for week, 20
minutes, 140 Hz) or placebo LDS 100
(no infrared light, 2 times for
week, 20 minutes, 140 Hz) (1:1) for
six months (Figs. 1 and 2).
Men and women visited the clinic
every 3 months, where they completed
a hair growth questionnaire and
investigators completed assessments
of scalp hair growth.
Every 6 months, photographs of scalp
hair were taken for hair counts and
for the expert panel assessments of
hair growth. Reports of adverse
events were collected throughout the
studies.

6-months extension studies
Men and women completing the initial
6-months, placebo controlled studies
were eligible to enrol in one
consecutive, 6-months,
placebo-controlled extension studies.
In these extension studies, men (N =
183) and women (N = 55) were
randomly assigned (as determined at
initial randomization) to treatment
with either LDS 100 (2 times for
week, 20 minutes, 140 Hz) or placebo
LDS 100 (no infrared light, 2 times
for week, 20 minutes, 140 Hz) (9:1),
such that subjects were randomized
to one of four groups that allocated
treatment to them during both the
initial 6-months studies and the
6-months extension studies:

A data
analysis, plan pre-specified all
primary and secondary hypotheses,
including combining data from the
initial 6-months studies to improve
precision of the estimates of the
treatment effect, as well as from
each of the 6-months controlled
extensions due to the small size of
the placebo groups in those studies.
Hair counts were assessed by the
difference between the count at each
time point versus the baseline count,
and mean hair count values for each
treatment group were determined
using SASTM Least Squares Means.
Each of the seven questions in the
patient self-assessment of hair
growth was assessed separately, and
the responses to each question at
each time point were taken as
assessments of changes from baseline.
The investigator assessment of hair
growth and the expert panel
assessments of global photographs
were assessed by comparison of mean
rating scores for each tratment
group at each time point, based on
the 7-point rating scale (minimum
value = -3.0 [greatly decreased];
maximum value = 3.0 [greatly
increased].
Hypothesis testing for hair counts,
individual patient self-assessment
questions, and investigator and
global photographic assessments was
performed using analysis of variance.
The primary efficacy analysis
population for this report was the
intention to treat population, which
included all subjects with at least
one day randomozed therapy and with
both baseline and at least one
post-baseline efficacy assessment.
For all efficacy analyses, missing
data were estimated by carring data
forward from the previous visit.
However, no data were carried
forward from the baseline evaluation,
or between the initial 6-months
study and the 6-months extension
study.
A secondary population for analysis
of efficacy included only the data
from the cohort of subjects who
completed the 1-year study.
Safety analyses were based on all
subjects with at least one day of
randomized therapy. The safety
analyses focused on the biochemical
parameters, using analysis of
variance, and on adverse experience
reports.

Results

Patient
accounting and baseline
characteristics

Patient
accounting is summarized in Figure
1. A summary of baseline
characteristics for man and women
who entered the extension study (2nd
6-months) is presented by treatment
group in Table I. Demographics and
baseline caharacteristics were
comparable among the four treatment
groups.

Hair counts

In the group
that received LDS 100 for all 12
months (LDS 100
LDS
100), there were significant
increases in hair counts over 1 year
(p < 0.001 versus baseline for all
time points), which reached a
maximal increase at month 6,
declined somewhat thereafter but
remained above baseline throughout,
with a mean increase of hairs at
month 12 (Fig. 3).

In contrast,
in the group that received placebo
for all 12 months (Placebo
Placebo), there was a progressive
decline in hair counts over 1 year,
culminating in a mean decrease from
baseline of hairs at month 12 (Fig.
3).

For the group
crossed over from Placebo to LDS 100
after 6 months (Placebo
LDS
100) there was a decrease in hair
count during the months of placebo
treatment. This initial loss of hair
on placebo was followed by
significant increases in hair count
during treatment with LDS 100
through month 12 (Fig. 3). Increases
in hair count during LDS 100
treatment in this group were
generally sustained over time,
although the increases compared to
baseline were consistently less than
those observed in the LDS 100
LDS 100
group at comparable time points,
with the difference being similar in
magnitude to the amount of hair loss
sustained during the year of placebo
treatment.

For the group
that received LDS 100 for 1st 6
months, was crossed over to placebo
for 2nd 6 months (LDS 100
Placebo), the beneficial effect on
hair count seen during the first
6-months of LDS 100 treatment was
reversed after 6 months of placebo
treatment (Fig. 3).

Patient
self-assessment

For each of
the seven questions in the patient
self-assessment questionnaire,
treatment with LDS 100 (LDS 100
LDS
100) was superior to treatment with
placebo (Placebo
Placebo) at each time point (p <
0.001 for all between-group
comparisons).

The LDS 100
LDS 100
group demonstrated significant (p <
0.001) improvement from baseline at
each time point for each question,
with the exception that there was no
significant difference from baseline
at the month 6 time point for
Question 5a (assessment of
satisfaction with appearance of the
frontal hairline), where as the
Placebo
Placebo group generally demonstrated
deterioration from baseline over
time.

For each of
the seven questions, a greater
proportion of LDS 100- versus
placebo-trated subjects reported an
improvement from baseline, with the
difference between groups increasing
over time (Table II).

In the Placebo
LDS 100
group, there was generally sustained
improvement following 6 months of
placebo treatment for each question
during the period of LDS 100
treatment (p < 0.001), although, as
with hair counts, this improvement
was less than that seen in the LDS
100 LDS
100 group at comparable time points.

For the LDS
100
Placebo group, partial to complete
reversibility of the beneficial
effect of LDS 100 was observed for
six of the seven questions after 6
months of placebo treatment (2nd
6-months).

Investigator assessment

Based on the
investigator assessment, treatment
with LDS 100 (LDS 100
LDS
100) was superior to treatment with
placebo (Placebo
Placebo) at each time point (p <
0.001, all comparisons).

The Placebo
LDS 100
group showed improvement during the
period of LDS 100 therapy, although
as with hair counts and patient
self-assessment the magnitude of
this improvement was less than that
seen in the LDS 100
LDS 100
group at comparable time points.
For the LDS 100
Placebo
group, there was initial improvement
during the first year of LDS 100
treatment, followed by a plateau
during the 6-months of placebo
treatment.

Global photographic assessment

Based on the
global photographic assessment,
treatment with LDS 100 (LDS 100
LDS
100) was superior to treatment with
placebo (Placebo
Placebo) at each time point (p <
0.001, all comparisons).

At month 12,
48% of LDS 100-treated subjects were
rated as slightly, moderately, or
greatly improved compared to 6% of
placebo-treated subjects.

Viewed in the
context of maintaining visible hair
from baseline, 90% of subjects
treated with LDS 100 demonstrated no
further visible hair loss by this
assessment, compared to 25% of
patients on placebo.
Conversely, 75% of subjects treated
with placebo demonstrated futher
visible hair loss by this assessment
at 1 year, compared to 10% of
subjects on LDS 100 (Fig. 5).

In contrast,
the Placebo
Placebo
group demonstrated progressive
worsening by global photographic
assessment through month 12.

The Placebo
LDS 100
group also demonstrated sustained
improvement in mean score during the
period of LDS 100 treatment from
month 6 to month 12 (p < 0.001),
although, as with the three other
efficacy measures, the magnitude of
improvement was less than that seen
in the LDS 100
LDS 100
group for comparable time points.

For the
Placebo
LDS 100 group, the beneficial effect
of LDS 100 was reversed after 6
months of placebo treatment (p <
0.001).

Global
photographs of representative
subjects from the Placebo
Placebo
and LDS 100
LDS 100
groups who were rated by the expert
panel as having decreased or
increased hair growth from baseline
are shown in Figure 6.

Adverse Event

Clinical
adverse experiences that were
considered by the investigator to be
possibly or definitely
treatment-related and that occurred
in at least 1% of subjects are
summarized in Table III.

As reported
previously, in the first 6-months a
slightly higher proportion of LDS
100 than placebo subjects reported
treatment-related adverse
experiences related to itching and
inflammation (Table III),
discontinued the studies due these
side effects. These side effects
resolved after discontinuation and
also resolved in most subjects who
reported them but remained on
therapy with LDS 100. The adverse
experience profile for subjects
continuing in the extension studies
was similar to that of the initial
studies (Table III).

Discussion

The data from
this study and its long-term
extension represent the longest
reported controlled observations in
men with MPHL and women with FPHL.

The combined
analysis demonstrated that long-term
tretament with LDS 100 led to
significant and durable improvements,
compared to both baseline and
placebo, in scalp hair in men with
MPHL and in women with FPHL. Hair
counts increased over the first
6-months of treatment with LDS 100,
with improvement above baseline
maintained over 1 year. In contrast,
the placebo group progressively lost
hair over 1 year, confirming the
natural progression of hair loss in
this disorder due to the conyinued
miniaturization of scalp hair. Thus,
the treatment effect of LDS 100 on
hair count relative to placebo
increased progressively over time,
leading to a net improvement for LDS
100-treated subjects hairs compared
to placebo at one year. Most (65%)
LDS 100-treated subjects had
increases in hair counts at one year,
compared to none of the
placebo-treated subjects, but even
for those LDS 100-treated subjects
with less hair by hair count at one
year, the magnitude of loss was less
than that observed in the placebo
group. these data support that the
progression of hair loss observed in
placebo-treated subjects was
significantly reduced by treatment
with LDS 100.

Based on the
predefined endpoints utilizing
photographic methods (hair counts,
and global photographic assessment),
peak efficacy was observed at 6
months to 12 months of treatment
with LDS 100. This observation of an
apparent peaking effect is likely
due, in part, to the
previously-reported beneficial
effects of LDS 100 on the hair
growth cycle based on a
phototrichogram study. In that study,
initiation of LDS 100 treatment was
shown to increase the number of
anagen-phase hairs and to increase
the anagen to telogen ratio,
consistent with normalization of the
growth cycles of previously
miniaturized hairs.

Consistent
with these results, LDS 100
treatment was also shown to increase
the growth rate and/or thikness of
hairs, based on analysis of serial
hair weight measurements. Because
these beneficial changes in the hair
growth cycle are dependent on when
therapy with LDS 100 is initiated
and occur rapidly, the affected
hairs are driven to cycle in a
synchronous manner. If these hairs
have somewhat similar anagen phase
durations, they would enter telogen
phase as the anagen (and catagen)
phase ended, followed by subsequent
shedding, in a partially
synchronized fashion. This would be
expected to produce a gradual
decline from peak hair count after a
period of time equal to the average
anagen phase duration. Eventually,
as subsequent growth cycles recurred,
these hairs would be expected to
become increasingly independent,
thereby losing their synchronous
character as their growth cycles
further normalized over time,
leading to a sustained increase in
hair count at a plateau above
baseline, as suggested by the 1 year
data presented here.

Patient
self-assessment of hair growth
provides a mechanism for each
subject to judge the benefits of
treatment under controlled and
blinded conditions. This
questionnaire asks specific
questions about the patient’s hair
growth or loss and his degree of
satisfaction with the appearance of
his hair compared to study start.
While a placebo effect was observed
with this instrument, as is typical
of patient questionnaire data,
results consistently demonstrated
that subjects treated with LDS 100
had a more positive self-assessment
of their hair growth and
satisfaction with their appearance
than subjects treated with placebo,
with the majority of LDS 100-treated
subjects reporting satisfaction with
the overall appearance of their
scalp hair at 1 year. Consistent
with the findings of another study
in which LDS 100 was evaluated in
subjects with predominantly frontal
MPHL, patients’ satisfaction with
the appearance of their frontal
hairline was improved by treatment
with LDS 100 in the present study.

The
investigators’ assessment are based
on observations of subjects seen in
the clinic and provide a clinically
relevant assessment of the patient’s
hair growth or loss since study
start. These assessments
demonstrated a sustained benefit of
LDS 100 treatment over 1 year.

As with the
patient self-assessment, the
investigator assessment had a
greater placebo effect than the more
objective
endpoints of hair count and global
photographic assessment. Such an
effect is not inusual in
double-blind, placebo-control led
studies, and is often due to general
expectation bias on the part of the
patient’s treating physician.

Despite this
apparent placebo effect, the
beneficial effects of LDS 100 were
demonstrated by the clinical
assessment made by the investigators
in these studies. In contrast to the
investigator assessment, the blinded
comparison of paired pre- and
post-treatment global photographs by
the expert panel, which also
assessed change from baseline,
demonstrated minimal, if any,
placebo effect.
Based on this assessment, LDS 100
treatment led to maintenance of
improvement above baseline in scalp
hair growth and scalp coverage over
one year, while placebo subjects
progressively worsened.

Treatment with
LDS 100 for one year led to
sustained protection against further
visible hair loss in nearly all
(90%) subjects, while further
visible hair loss as evident in most
(75%) subjects treated with placebo
over the same time period.

While the
number of patients remaining in the
study declined over time and the
size of the placebo group was
limited in the extension study, the
results of analyses that included
either all available patients at
each time point or only the cohort
of patients with data at month 12
were consistent and supported a
sustained benefit in hair growth for
subjects receiving LDS 100 compared
with placebo.

Additionally,
examination of data from
placebo-treated subjects in all
cohorts demonstrated the continued
loss of scalp hair that occurs in
untreated subjects with MPHL and
FPHL. Thus, regardless of the cohort
examined, the long-term data from
these studies consistently
demonstrated a beneficial effect of
LDS 100 compared with placebo for
men with MPHL and women with FPHL.

Moreover, this
beneficial effect increased over
time due to the progressive increase
in the net treatment effect of LDS
100 compared with placebo.

The safety
data from the one year of controlled
observations in the current study
provide reassurance that long-term
use of LDS 100 in men with MPHL and
women with FPHL is not associated
with an increase in the incidence of
adverse experiences or any new
safety concerns.

A few subjects
in the current studies experienced
reversible itching and inflammation.
No other significant adverse effects
of LDS 100 were observed in the
patient population evaluated in the
current studies.

This excellent
safety profile of long-term use of
LDS 100 is consistent with the
experience with the infrared light
at five times the dose used in the
present study that has been
well-documented in large clinical
trials and post-marketing
surveillance in men and women.
In summary, treatment with LDS 100
over one year increased scalp hair
as determined by scalp hair counts,
patient self-assessment,
investigator assessment, and global
photographic assessment, when
compared with placebo. In contrast,
data from the placebo group
confirmed that without treatment
progressive reductions in hair count
and continued loss of visible hair
occurs.

Long-term
treatment with LDS 100 was generally
well tolerated. The results of these
studies demonstrate that chronic
therapy with LDS 100 leads to
durable improvements in hair growth
in men with MPHL and women with FPHL
and slows the further progression of
hair loss that occurs without
treatment.
References